This application responds to research objective 14 "Functional Senescence" of PAR-02-049. Neurons of the central nervous system tightly regulate their intracellular free Ca 2+concentration. Small changes in the cytosolic Ca 2+ concentration and different patterns of Ca 2+transients are used to mediate important functional processes. In neurons both entry of extracellular Ca 2+ and release of Ca 2+ from intracellular stores are directly coupled to the activation of glutamate receptors and mediate physiological and pathophysiological processes. For the development of early-onset inherited AIzheimer's Disease (AD) and age-related cognitive impairment, numerous reports indicate that changes in the intracellular Ca 2+ concentration promote pathogenesis. The present application will test the hypothesis that the interaction of a group of intracellular Ca 2+ channels, ryanodine receptors, with presenilin-1 leads to a modulation of ryanodine receptor channel function. We further hypothesize that this interaction is mediated through specific binding sites that can be affected by presenilin-1 mutations, but can also be used as the target of potential pharmacological interventions aiming at modifying the presenilin-1 - ryanodine receptor interaction. Experiments will use a combination of single channel electrophysiology and spectrofluorimetric Ca 2+release assays. The specific aims of this proposal are to determine the modulation of biophysical and pharmacological characteristics of ryanodine receptors by presenilin-1 and to measure changes of ryanodine receptor activity after binding to mutated presenilin-1 as found in AD. These studies will allow the determination of mechanisms that influence intracellular Ca 2+ concentrations in neurons and that may play a crucial role in the development of the pathophysiology of Alzheimer's Disease and age-related cognitive impairment. Thus, potential new targets for treating those devastating conditions affecting the aging population may be identified.